Project Summary/Abstract Hesperos will construct and test microscale multi-organ systems with recirculating blood and cerebral spinal fluid surrogates that will give insights to the responses of various Alzheimer?s phenotypes to drugs as well as the influence of peripheral effects on AD progression, specifically ApoE variants. We seek to leverage Dr. Morgan?s research on Alzheimer?s and aging combine it with Drs. Shuler and Hickman?s research on human-on-a-chip systems to better understand the disease and its mechanism of action and to test efficacy and toxic side effects of treatments. We will investigate both small molecules and biologics, on human organ modules in the same multi-organ system using iPSC derived non-diseased (ND) and Alzheimer?s phenotypes. A preclinical model that can accurately predict human response should not only lead to better decisions on which Alzheimer?s treatment to take into human clinical trials, but also for personalized medicine applications. By eventually comparing acute to chronic effects, the model will enable prediction of clinical trial success using pharmacodynamic (PD) models to inform clinical disease trials from preclinical studies. Current human-based in vitro toxicity studies have the limited capacity to predict functional changes that have been the demise of many potential therapeutics. We have previously constructed platforms demonstrating the integration of multiple organ mimics for acute responses and will build upon that technology. In this Phase I proposal we will build a 3-organ system composed of cortical neuronal components to utilize long term potentiation (LTP) as a functional readout, which will be separated by a functional blood brain barrier (BBB) from a liver model. The liver will result in a model with not only parental drugs but metabolites in the blood and the BBB will model the penetration of the drug and its metabolites into the brain. We will use isogenic methods to introduce the APP mutation into iPSCs and screen and select for ApoE3 and ApoE4 variants to test in the system vs. control. The effect of mutation and variant in both neurons and liver will give insight to peripheral as opposed to CNS effects. Development of a low cost, easy to use multi-organ system to assay drugs for AD would facilitate widespread usage and maximize the benefit to the drug development community as well as for efficacy and toxicological evaluations for patient specific treatment. The integrated use of these pre-clinical test systems and PBPK/PD models provides a powerful tool for evaluating the dynamic interaction between drugs, aging biological system and disease and will facilitate rationale drug development and clinical trial design. Our team contains all of the skill sets to achieve the goals on the grant. In Phase II, we will expand our experiments from acute to chronic and then extend this to AD patient specific samples for personalized medicine applications.